1. Technical Field
The present invention relates to novel aniline derivatives or salts thereof, production methods thereof, synthetic intermediates therefor, and use of the aniline derivative as a pharmaceutical product. More particularly, the present invention relates to a kininogenase inhibitor (enzyme inhibition) and an agent for the prophylaxis or treatment of various diseases for which the enzyme inhibition is effective.
2. Brief Description of the Related Art
The kallikrein-kinin system plays various physiological functions in living organisms, and functional promotion of a kallikrein-kinin production system is considered to be deeply involved in the pathology of inflammatory allergic diseases such as asthma, rhinitis, arthritis and the like, pain, sepsis, tissue injury and the like (Kinin and angiotensin-molecular mechanism in vivo control, ed. Hisayuki Matsuo, Makoto Katori, Kodansha, Tokyo (1994)). The kallikrein-kinin system is a series of reaction system, wherein the kallikrein enzyme acts on kininogen, a substrate, to cause limited proteolysis, whereby kallidin and bradykinin are produced, then kininase I acts thereon to produce des-Arg10-kallidin and des-Arg9-bradykinin. These kinins including kallidin, bradykinin, des-Arg10-kallidin, des-Arg9-bradykinin and the like are active peptides which are physiologically active substances in living organisms, and are known to vary in sensitivity to kinin receptors, depending on the kind of these receptors. As the kallikrein-kinin system reaction pathway, two kinds are known depending on the kind of kallikrein enzyme, which are a plasma kallikrein-kinin system (system wherein plasma kallikrein acts on high molecular weight kininogen) and a tissue kallikrein-kinin system (system wherein tissue kallikrein acts on low molecular weight kininogen). It is assumed that the kinins produced by these pathways act on kinin B2 receptors, which are constitutively expressed in many tissues, to cause most physiological actions, and also act on kinin B1 receptors, which are induced to express by stimulation such as inflammatory response, tissue injury and the like, thus being involved in the retention of inflammatory response and reinforcement algetic reaction associated therewith (Biochimica et Biophysica Acta, 1495, 69-77 (2000)). Expression of B1 receptors in the spinal cord of normal mouse is known to be involved in the acute pain during non-inflammation (PNAS, 97, 8140-8145 (2000)).
The kinins are peptides that are produced and released from kininogen by limited proteolysis by the above-mentioned kininogenase such as kallikrein and the like, and are endogenous mediators useful for inflammatory reactions. For example, kallidin, bradykinin, des-Arg10-kallidin and des-Arg9-bradykinin can be mentioned. The main actions thereof are 1) induction of pain, 2) formation of exudates and edema due to increased vascular permeability, 3) contraction of bronchial smooth muscle and intestinal smooth muscle, 4) decreased blood pressure and increased blood flow due to vasodilating action in arteriola, and the like.
The kinins are known to promote production and release of mediators involved in some actions of kinins, such as prostaglandins (PG) etc., by the activation of phospholipase A2. It is known that the PGs themselves do not cause pain or vascular permeability elevating action at a concentration found in inflammatory tissues, but particularly potentiate pain and permeability elevating action when the above-mentioned kinins coexist.
Moreover, involvement of kinins is shown, for example, in the following conditions. Examples of the publications are recited.
1) The state relating to gastrointestinal tract disease: for example, inflammatory bowel disease (Immunopharmacology, 43, 103-108 (1999), Digestive Diseases and Sciences, 44, 845-851 (1999), Japanese Journal of Pharmacology, 90, 59-66 (2002)), and, acute pancreatitis (British Journal of Pharmacology, 139, 299-308 (2003), British Journal of Pharmacology, 137, 692-700 (2002))
2) The state relating to pain: for example, pain (Life Sciences, 61, 1253-1259 (1997), Brain Research, 969, 110-116 (2003))
3) The state relating to bronchoconstriction: for example, bronchitis observed in acute allergic reaction in early asthma and inflammatory phase of asthma, and the resulting bronchial obstruction (European Journal of Pharmacology, 467, 197-203 (2003), Am J Physio Lung Cell Mol Physiol, 286, L734-L740 (2004), Am Res Respir Dis, 142, 1367 (1990), Am Res Respir Dis, 143, 767 (1991))
4) The state relating to allergic inflammation: for example, particularly allergic rhinitis (Am Rev Respir Dis, 137, 613 (1988), Journal of Clinical Investigation, 72, 1678 (1983), Journal of Immunology, 137, 1323 (1986)) and conjunctivitis (Infection and Immunity, 55, 2509 (1987), Nature, 337, 385 (1989))
5) The state relating to inflammatory disease: for example, arthritis (Scand J Rheumatol, 31, 38-40 (2002), Pharmacol Ther, 94, 1-34(2002))
6) The state relating to edematous disease: for example, brain edema (Brain Res, 950, 268-278 (2002))
7) The state relating to organ fibrosis: promotion of fibrillization accompanied by collagen production (Am J Physiol Heart Circ Physiol, 279, H2829-H2837 (2000), Journal Biological Chemistry, 275, 12475-12480 (2000))
8) The state relating to vasodilation and acute hypotension: for example, sepsis, anaphylactic shock and hypovolemic shock; carcinoid syndrome and dumping syndrome (American Journal of Physiology, 260, G213 (1991), Circ Shock, 27, 93 (1989))
9) The state relating to hemorrhage: for example, hemorrhage (Ann Thorac Surg, 68, 473-478 (1999))
10) The state relating to cell proliferative disease: for example, cell proliferative disease (American Journal of Pathology, 159, 1797-1805 (2001), Idrugs, 6, 581-586 (2003)) and inhibition of neovascularization (Laboratory Investigation, 82, 871-880 (2002))
The “kininogenase” is one kind of serine proteases that produce kinins by limited proteolysis of kininogen, a substrate. Several kinds of kininogenase are known, which are largely divided into “tissue kallikrein” and “plasma kallikrein”.
(1) The “tissue kallikrein” (TK) is a protein having a molecular weight of about 30,000, and produces and releases kallidin (KD) as a kinin by specifically acting on a low molecular weight kininogen (LMWK), which is a substrate. It is also known that the tissue kallikrein is not present in plasma, but present in various expression tissues. For example, it is found in pancreas, kidney, intestine, salivary gland, urine and the like in human (Endocrine Reviews, 22, 184-204 (2001), Biochemical Journal, 307, 481-486 (1995)), and rat (Journal of Biological Chemistry, 271, 13684-13690 (1996)).
(2) The “plasma kallikrein” (PK) is a protein having a molecular weight of about 100,000, and present in plasma as an inactive enzyme. It is activated by blood coagulation factor XIIa, and produces and releases bradykinin as a kinin by acting on a high molecular weight kininogen, which is a substrate with higher affinity. Plasma kallikrein is quickly and efficiently inhibited by a C1 inactivator and an endogenous inhibitory factor known as α2 macroglobuline.
Kininogen is an endogenous natural substrate of kininogenase enzyme, and is classified into two kinds. (1) The low molecular weight kininogen (LMWK) has a molecular weight within the range of 50,000 to 70,000 depending on the species of origin and formation process of sugar chain.
(2) The high molecular weight kininogen (HMWK) is a protein having a molecular weight within the range of 88,000 to 114,000, and plays a role of a cysteine protease inhibitory factor besides the precursor of kinin.
The above-mentioned two kinds of kininogens are translated from respective mRNAs derived from the same gene and consist of an H chain (Heavy chain or N-terminal), a kinin region and an L chain (Light chain or C-terminal). HMWK has an L chain (molecular weight 45K) longer than an L chain (molecular weight 4.8K) of LMWK, and the two are different on this point.
For example, the detail of the sequence at the cleavage site of human kininogen by plasma kallikrein (PK) and tissue kallikrein (TK) is shown in FIG. 1, and the detail of the cleavage site by kininase I is shown in FIG. 2.
As shown in FIG. 1, when the kinin C-terminal is to be released, PK and TK act on the same cleavage site (I) of the 389th Phe and 390th Arg of human kininogen. On the other hand, when the kinin N-terminal is to be released, PK acts on the cleavage site (II) of the 381st Arg and the 380th Lys to produce bradykinin, and TK acts on the cleavage site (III) of the 379th Met and the 380th Lys to produce kallidin. The bradykinin and kallidin produced in this way act on the kinin B2 receptor to exhibit a physiological action. As shown in FIG. 2, in bradykinin and kallidin, C-terminal Arg is cleaved with kininase I to produce des-Arg9-bradykinin and des-Arg10-kallidin, respectively, which mainly act on kinin B1 receptor to exhibit a physiological action.
As an example of a compound having a trifluoromethylaniline-like skeleton, WO2003/022809 discloses a compound represented by the following formula. While the compound of the following formula has a urea bond, the compounds represented by the formulas (A), (B), (C) and (H) of the present invention are markedly different in that the corresponding part is an amide bond, an ether bond and the like. This patent reference describes, moreover, that a compound of the following formula is useful as a therapeutic drug having an analgesic, inflammatory effect via a vanilloid receptor (VR1) antagonistic action. However, the action of the compound of the present invention is based on kininogenase inhibition, and an effect different from the VR1 antagonistic action is expected.

In addition, WO2003/002553 discloses a compound having a dipeptidyl-peptidase IV inhibitory action, which is represented by the following formula, as a therapeutic drug for allergy, inflammation or asthma. However, the compounds represented by the formulas (A), (B), (C) and (H) of the present invention are structurally markedly different in that the amine moiety is an amide bond, an ether bond and the like. This patent reference does not at all describe or suggest the action based on kininogenase inhibition.

Moreover, WO2002/051836 discloses a compound having a dipeptidyl-peptidase IV inhibitory action, which is represented by the following formula, as a therapeutic drug for inflammatory enteritis or chronic rheumatoid arthritis. However, the compounds represented by the formulas (A), (B), (C) and (H) of the present invention are structurally markedly different in that the amine moiety is an amide bond, an ether bond and the like. This patent reference does not at all describe or suggest the action based on kininogenase inhibition.

WO97/04779 also discloses a compound having phosphodiesterase IV inhibitory action, which is represented by the following formula, as a therapeutic drug for allergy or inflammation. However, the compounds represented by the formulas (E) and (E′) of the present invention are structurally markedly different in that the quinolone moiety is reduced. In addition, this patent reference does not at all describe or suggest the action based on kininogenase inhibition.

Moreover, the following compound (CAS No. 259196-60-6) is structurally similar to the compounds represented by the formulas (E) and (E′) of the present invention and can be purchased as a reagent. However, its use as a pharmaceutical agent is not reported.

In addition to the above mentioned compounds, various compounds having an aniline-like skeleton have been reported (US2003/0055031; Dawei Ma et al., “Journal of the American Chemical Society”, (US), 1998, vol. 120, No. 48, pp. 12459-12467; Fuk Yee Kwong et al., “Organic Letters”, (US), 2002, vol. 4, No. 4, pp. 581-584; Hiroki Takahata et al., “Chemical & pharmaceutical bulletin”, (JP), 1981, vol. 29, No. 4, pp. 1063-1068; Kevin W. Anderson et al., “Organic Letters”, (US), 2002, Vol. 4, No. 3, pp. 459-461; Dolores Edmont et al., “Bioorganic & Medicinal Chemistry Letters”, (UK), 2000, vol. 10, No. 16, pp. 1831-1834). However, these compounds are structurally different from the compounds of the present invention. Furthermore, they have uses which are different from a pharmaceutical agent, and do not envisage the kininogenase inhibitory action of the compounds of the present invention.